Digestive Diseases and Sciences

, Volume 52, Issue 6, pp 1438–1441

Pneumocystis Pneumonia During Combined Therapy of Infliximab, Corticosteroid, and Azathioprine in a Patient with Crohn’s Disease

Authors

  • Soichi Itaba
    • Department of GastroenterologyKitakyushu Municipal Medical Center
  • Tsutomu Iwasa
    • Department of GastroenterologyKitakyushu Municipal Medical Center
  • Yojiro Sadamoto
    • Department of GastroenterologyKitakyushu Municipal Medical Center
  • Toshifumi Nasu
    • Department of GastroenterologyKitakyushu Municipal Medical Center
  • Tadashi Misawa
    • Department of GastroenterologyKitakyushu Municipal Medical Center
  • Koji Inoue
    • Department of Respiratory MedicineKitakyushu Municipal Medical Center
  • Hidehiko Shimokawa
    • Department of Chest SurgeryKitakyushu Municipal Medical Center
    • Department of Medicine and Bioregulatory ScienceGraduate School of Medical Sciences, Kyushu University
  • Ryoichi Takayanagi
    • Department of Medicine and Bioregulatory ScienceGraduate School of Medical Sciences, Kyushu University
CASE REPORT

DOI: 10.1007/s10620-006-9575-5

Cite this article as:
Itaba, S., Iwasa, T., Sadamoto, Y. et al. Dig Dis Sci (2007) 52: 1438. doi:10.1007/s10620-006-9575-5

Keywords

Crohn’s diseaseInfliximabPneumocystis jiroveciPneumocystis pneumoniaCorticosteroid

Introduction

Pneumocystis pneumonia (PCP) is one of the most frequent and severe opportunistic infections in immunocompromised patients. In recognition of its genetic and functional distinctiveness, the organism that causes human PCP has now been designated Pneumocystis jiroveci [1].

The number of patients who are receiving chronic immunosuppressive medication or have an altered immune system and are thus at risk of PCP is increasing rapidly [2]. A recent report indicated that inflammatory disorders represent nearly 20% of the underlying diseases associated with PCP in HIV-negative patients [3]. Furthermore, patients with Wegener’s granulomatosis and systemic lupus erythematosus show high risks of developing PCP among patients with inflammatory disorders [4]. Although corticosteroids and other immunosuppressive drugs are frequently administered to patients with Crohn’s disease, there is only one report of a Crohn’s disease patient who developed PCP before infliximab was introduced for the treatment of Crohn’s disease [5].

Infliximab, a chimeric anti-tumor necrosis factor α (TNFα) monoclonal antibody, binds to TNFα with a high affinity, thereby neutralizing its biological activity [6]. Infliximab induces remission in patients with moderately to severely active Crohn’s disease and can reduce the requirement for corticosteroid treatment [7]. A recent study demonstrated that infliximab is also effective in patients with moderate to severe ulcerative colitis [8]. The incidences of serious infections across infliximab-treated patients and placebo-treated groups were reported to be similar in the ACCENT 1 trial [7]. Colombel et al. reported that infections were the most frequent cause of serious adverse events associated with the use of infliximab among their patients, and that 41 (8.2%) patients had infectious events considered to be at least possibily related to infliximab among 500 Crohn’s disease patients treated with infliximab [9]. Serious infections, such as sepsis, miliary tuberculosis, disseminated coccidioidomycosis, histoplasmosis, listeriosis, and aspergillosis, have been observed in infliximab-treated patients and have led patient death in some instances [10]. Following the introduction of infliximab administration for the treatment of Crohn’s disease, three cases of PCP related to infliximab were reported within a relatively short time period [1113]. Here we report a case of PCP infection that followed combined therapy with infliximab, azathioprine, and corticosteroid and presented delayed recovery in a patient with Crohn’s disease.

Case report

A 57-year-old Japanese woman was admitted to our hospital with a 5-day history of fever, nonproductive cough, and shortness of breath. Her history of illness was appendicitis and gastric ulcer. She had a 21-year history of Crohn’s disease. She was maintained with enteral nutrition, mesalazine, oral corticosteroid (prednisolone, 25 mg), and azathioprine (50 mg). In September 2004, low-grade fever and general malaise continued, without any signs of infection. Thus, infusion of infliximab (5 mg/kg) for induction was initiated on 6 October 2004. A purified protein derivative skin test was negative and the patient’s chest radiography was normal before the infusion of infliximab. After two doses of infliximab (0 and 2 weeks) with total parenteral nutrition, her general condition improved and the fever was alleviated. Therefore, the scheduled infusion of infliximab was skipped at 6 weeks. However, her general condition worsened again, and a second induction therapy with infliximab was initiated on 27 December 2004. Two weeks after the second dose of infliximab (at 2 weeks), the administration of azathioprine was discontinued, since laboratory analyses revealed a decreased leukocyte count (1790 cells/μl) and lymphocyte count (340 cells/μl).

At 3 weeks after these two doses of infliximab, the patient was admitted to hospital. She had not received prophylaxis for PCP prior to her admission. A physical examination on admission showed tenderness in the right and left lower quadrants of the abdomen. Findings on lung auscultation were normal. Laboratory analysis on admission revealed a leukocyte count of 4370 cells/μl, lymphocyte count of 175 cells/μl, and hemoglobin level of 10.2 g/dl. Serum C-reactive protein and β-d-glucan, a serological marker of PCP [14], were 3.5 mg/dl and 91.8 pg/ml (<11 pg/ml), respectively. HIV antibody was negative. The patient’s PaO2 was 64 mm Hg on room air, but her chest radiography was almost-normal on admission (Fig. 1). Thoracic computed tomography displayed dominant faint ground glass-like shadows in the inferior lobes of the lungs. A bronchoscopy was carried out, and Pneumocystis jiroveci was detected in the bronchoalveolar lavage (BAL) fluid using Grocott’s methenamine silver stain. No other pathogens were identified in the BAL fluid.
https://static-content.springer.com/image/art%3A10.1007%2Fs10620-006-9575-5/MediaObjects/10620_2006_9575_Fig1_HTML.jpg
Fig. 1

Chest radiography is almost-normal on admission

Oral administration of trimethoprim/sulfamethoxazole was begun on the first hospital day. Pulsed intravenous methylprednisolone was added on the second hospital day, since hypoxia developed. On the eighth hospital day, hematochezia began, and a colonoscopy was performed. The colonoscopy revealed multiple longitudinal ulcers on the transverse colon, indicating active Crohn’s disease. On hospital day 13, oral trimethoprim/sulfamethoxazole was changed to intravenous administration, since oral trimethoprim/sulfamethoxazole was not effective. On hospital day 18, serum β-d-glucan was elevated to 515.8 pg/ml. The patient’s respiratory condition deteriorated, and the bilateral lung fields were occupied by pulmonary infiltrates on chest radiography (Fig. 2). Since intravenous trimethoprim/sulfamethoxazole was not effective either, the therapy was replaced by intravenous pentamidine. The patient presented with leukocytopenia, indicating that pentamidine was not effective, and the therapy was therefore replaced again, by intravenous trimethoprim/sulfamethoxazole, on hospital day 26. Her respiratory condition gradually improved after replacement of the drug. On hospital day 42, her chest radiography had improved dramatically compared with the worst previous radiography, but she suddenly developed pneumothorax that required chest tube drainage. Although the chest tube drainage was continued for 1 week, air leakage from the pleural cavity continued and the patient underwent surgery. The surgical findings revealed perforation from a microabscess. Resection of the piece of lung tissue containing the perforation site, and closure with pleura, was performed. Recovery after the surgery was uneventful. The patient underwent rehabilitation, since her respiratory function and muscle power had deteriorated. She was discharged 113 days after admission.
https://static-content.springer.com/image/art%3A10.1007%2Fs10620-006-9575-5/MediaObjects/10620_2006_9575_Fig2_HTML.jpg
Fig. 2

Chest radiography reveals diffuse pulmonary infiltrates in the bilateral lung fields (right < left) on hospital day 25

Table 1

Data on pneumocystis pneumonia during administration of infliximab

Reference

Year

Age/gender

Total doses of infliximab

Concomitant drug(s)

Lymphocyte count (cells/μl)

Clinical course

Seddik et al. [11]

2004

29/M

1

PSL (60 mg), AZA (150 mg)

505

Alive

Velayos & Sandborn [12]

2004

19/M

14

AZA (75 mg)

ND

Alive

Kaur & Mahl [13]

2004

59/M

2

PSL (40 mg)

910

Dead

Present case

 

57/F

4

PSL (25 mg),

175

Alive

    

AZA (50 mg)

  

Note. PSL, prednisolone; AZA, azathioprine; ND, not described.

Discussion

In the present case, we used corticosteroid, azathioprine, and infliximab for the treatment of active Crohn’s disease. Corticosteroids remain the mainstay of treatments for active Crohn’s disease but have many side effects. Corticosteroid use is thought to be the most common predisposition for developing PCP [15]. As experienced in our case, glucocorticosteroid dependency, which is defined as a relapse of symptoms within 30 days of treatment or during dose tapering, that does not allow discontinuation of the drug is clinically important. The percentage of patients with corticosteroid dependency ranges from 20% to 36% [16]. Therefore, we need to add other drugs with proven corticosteroid-sparing effects during corticosteroid treatment of corticosteroid-dependent Crohn’s disease patients.

Azathioprine is also widely used for the treatment of Crohn’s disease. A combination therapy with corticosteroid and azathioprine was reported to be superior to treatment with the corticosteroid alone in active Crohn’s disease [17]. Furthermore, corticosteroid-sparing effects of azathioprine were demonstrated in active Crohn’s disease [18]. The safety of azathioprine for the treatment of Crohn’s disease was confirmed in a study over a 30-year time period [19]. There is only one reported case of inflammatory bowel disease that developed PCP during antimetabolite immunosuppressive therapy with 6-MP (50 mg/day) alone [20].

Corticosteroid-sparing effects have also been proved for infliximab [21]. A three-dose induction regime of infliximab was more effective than a single dose [7]. We found only three reported cases of PCP during the use of infliximab for treatment of Crohn’s disease in a review of the English literature [1113]. The clinical data for these cases and the current case are reported in Table 1. The total doses of infliximab varied among the cases. Lymphocytopenia (<1000 cells/μl) was observed in all the cases, and the lymphocyte count was particularly low (175 cells/μl) in our case. One of the four cases died of PCP. Colombel et al. reported that the rate of infectious events was not correlated with the number of infusions of infliximab [9].

Prophylaxis criteria for PCP in patients without AIDS have not been well established in prospective controlled trials. Sepkowitz et al. suggested that immunosuppressed patients owing to an underlying disease or patients receiving other immunosuppressive therapy besides glucocorticoids at ≥ 20 mg/day for 4 weeks or more should receive prophylaxis [15]. The occurrence of PCP in patients with autoimmune inflammatory disorders was clearly associated with major lymphopenia secondary to immunosuppressive therapy, which was present in almost all the patients [22]. From these points of view, our patient should have received the prophylaxis for PCP.

Trimethoprim/sulfamethoxazole used at its full dose is a first-line treatment for PCP [23]. This drug is routinely used for 21 days for treatment of PCP in HIV-infected patients. However, 14–17 days of treatment is recommended for non-HIV-associated PCP [24]. TNF-α has important effects during PCP [23]. The clearance of Pneumocystis jiroveci is delayed when TNF-α is neutralized by antibodies in animals with PCP [23]. After a single infusion of infliximab, most patients receiving a 5 mg/kg dose still have a therapeutic concentration at 8 weeks but undetectable concentrations at 12 weeks [25]. In the present case, drugs for PCP were not effective until 7 weeks after the last administration of infliximab. Therefore, delayed recovery from PCP may have been associated with infliximab when the concentration of infliximab was still considered to be in the therapeutic range.

Pareja et al. reported that adjunctive high-dose corticosteroids accelerate recovery in patients with severe non-HIV-associated PCP [26]. However, whether or not adjunctive high-dose corticosteroids should be used for cases of PCP during administration of infliximab remains to be elucidated, since infliximab, an anti TNF-α antibody, itself suppresses the lung inflammation provoked by Pneumocystis jiroveci. Since the number of reported cases with PCP during the administration of infliximab is small, further investigations with a larger accumulation of cases are necessary.

Copyright information

© Springer Science+Business Media, LLC 2006